7. PROJECT SUMMARY Focal changes in bone, known as bone marrow lesions (BMLs, sometimes referred to as ?bone bruise? or ?bone marrow edema patterns?) are observed in cancellous bone using magnetic resonance imaging and are associated with joint degeneration. In multiple longitudinal studies the presence and/or enlargement of bone marrow lesions precedes cartilage degeneration, suggesting that alterations in bone physiology within a bone marrow lesion influence joint health. These findings and others suggest that bone marrow lesions may address the long-standing clinical need for an indicator of osteoarthritis that is present before irreversible joint degeneration. A critical barrier to understanding the pathophysiology of bone marrow lesions is that the changes in bone physiology within a BML are not understood because the only available histopathology of BMLs are taken from humans at the time of total joint replacement when joint degeneration is well established. Hence little is known about bone marrow lesions at early, reversible stages. To address this critical barrier, we have developed a rabbit model in which mechanical loading induces bone marrow lesions in vivo. In the proposed work we use this new model system to understand the mechanisms leading to the initiation and sustained development of a bone marrow lesion. Our global hypothesis is that mechanical loading stimulates bone resorption in cancellous bone that leads to the initiation of a BML which subsequently contributes to catabolic bone-joint crosstalk. In the proposed Exploratory/Developmental project we use the novel rabbit model to address the hypothesis that bone resorption is required for the initiation and sustained development of a bone marrow lesion. The work has a single Aim with two parts: Aim 1a) Determine the effects of inhibiting bone resorption on the initiation of a bone marrow lesion; Aim1b) Determine the effects of inhibiting bone resorption after a bone marrow lesion is established. The proposed work will determine contributors to the pathophysiology of bone marrow lesions and also test the idea that treatments that inhibit bone resorption can interrupt the initiation or sustained development of a bone marrow lesion.